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The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity., The human reference genome does not fully reflect human genetic diversity. Here, the authors analyse 338 human genome assemblies from diverse populations to identify missing sequences, define non-reference unique insertions and construct a Human Diversity Reference.

Background It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis. Methods The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic. Results We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29–4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40–6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64–6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22–3.51; P = 0.007). Conclusions Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation. Electronic supplementary material The online version of this article (10.1186/s12885-018-4229-5) contains supplementary material, which is available to authorized users.

Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P –8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P –3 . No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 ( P =7.5×10 –15 ), rs2681492 at ATP2B1 ( P =3.4×10 –7 ), rs11191593 at NT5C2 (1.1×10 –6 ), rs3824755 at CYP17A1 ( P =1.2×10 –6 ), and rs13149993 at FGF5 ( P =2.4×10 –4 ). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P MAP4 ( P =0.014) and rs1173771 at NPR3 ( P =0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 ( P =1.2×10 –5 ) and rs11191593 at NT5C2 ( P =1.1×10 –3 ), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 ( P =6.1×10 –3 ) and rs2681492 at ATP2B1 ( P =9.0×10 –3 ). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

This paper conducts performance evaluation for the ultra-tight integration of Global positioning system (GPS) and inertial navigation system (INS) by use of the fuzzy adaptive strong tracking unscented Kalman filter (FASTUKF). An ultra-tight GPS/INS integration architecture involves fusion of the in-phase and quadrature components from the correlator of the GPS receiver with the INS data. These two components are highly nonlinearly related to the navigation states. The strong tracking unscented Kalman filter (STUKF) is based on the combination of an unscented Kalman filter (UKF) and strong tracking algorithm (STA) to perform the parameter adaptation task for various dynamic characteristics. The STA is basically a nonlinear smoother algorithm that employs suboptimal multiple fading factors, in which the softening factors are involved. In order to resolve the shortcoming in a traditional approach for selecting the softening factor through personal experience or computer simulation, the Fuzzy Logic Adaptive System (FLAS) is incorporated for determining the softening factor, leading to the FASTUKF. Two examples are provided for illustrating the effectiveness of the design and demonstrating effective improvement in navigation estimation accuracy and, therefore, the proposed FASTUKF algorithm can be considered as an alternative approach for designing the ultra tightly coupled GPS/INS integrated navigation system.

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs* 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.

// Wen-Ling Liao 1, 2, * , Wen-Jane Lee 3, * , Ching-Chu Chen 4, 5, * , Chieh Hsiang Lu 6, 7, 8, * , Chien-Hsiun Chen 5, 9 , Yi-Chun Chou 9 , I-Te Lee 10, 11, 12 , Wayne H-H Sheu 10, 12, 13, 14 , Jer-Yuarn Wu 5, 9 , Chi-Fan Yang 9 , Chung-Hsing Wang 15, 16 , Fuu-Jen Tsai 5, 17, 18 1 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan 2 Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan 3 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan 4 Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan 5 School of Chinese Medicine, China Medical University, Taichung, Taiwan 6 Department of Internal Medicine, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi City, Taiwan 7 Department of Nursing, College of Nursing and Health Sciences, DAYEH University, Changhua, Taiwan 8 Department of Business management, College of Management, National Chung Cheng University, Chia-yi, Taiwan 9 National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 10 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans Hospital, Taichung, Taiwan 11 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 12 School of Medicine, National Yang-Ming University, Taipei, Taiwan 13 School of Medicine, National Defense Medical Center, Taipei, Taiwan 14 Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan 15 Department of Genetics and Metabolism, Children’s Hospital of China Medical University, Taichung, Taiwan 16 School of Medicine, China Medical University, Taichung, Taiwan 17 Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan 18 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Fuu-Jen Tsai, email: d0704@www.cmuh.org.tw Keywords: DPP-4 inhibitors, pharmacogenetics, Taiwanese, type 2 diabetes Received: January 29, 2016 Accepted: January 03, 2017 Published: February 01, 2017 ABSTRACT Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes ( T2D ). Despite DPP-4 inhibitors’ advantages, the patients’ therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors ( P < 1 × 10 -4 ) were identified at or near PRKD1 , CNTN3 , ASK, and LOC10537792. A SNP located within the fourth intron of PRKD1 (rs57803087) was strongly associated with DPP-4 inhibitor response ( P = 3.2 × 10 -6 ). This is the first pharmacogenomics study on DPP-4 inhibitor treatment for diabetes in a Taiwanese population. Our data suggest that genes associated with β-cell function and apoptosis are involved in the therapeutic effect of DPP-4 inhibitors, even in the presence of additional oral anti-diabetic drugs. Our findings provide information on how genetic variants influence drug response and may benefit the development of personalized medicine.

This paper presents a sensor fusion method for the Ultra-Tightly Coupled (UTC) Global Positioning System (GPS)/Inertial Navigation System (INS) integrated navigation. The UTC structure, also known as the deep integration, exhibits many advantages, e.g., disturbance and multipath rejection capability, improved tracking capability for dynamic scenarios and weak signals, and reduction of acquisition time. This architecture involves the integration of I (in-phase) and Q (quadrature) components from the correlator of a GPS receiver with the INS data. The Particle Filter (PF) exhibits superior performance as compared to an Extended Kalman Filter (EKF) and Unscented Kalman Filter (UKF) in state estimation for the nonlinear, non-Gaussian system. To handle the problem of heavy-tailed probability distribution, one of the strategies is to incorporate the UKF into the PF as the proposal distribution, leading to the Unscented Particle Filter (UPF). The combination of an adaptive UPF and Fuzzy Logic Adaptive System (FLAS) is adopted for reducing the number of particles with sufficiently good results. The GPS tracking loops may lose lock due to the signals being weak, subjected to excessive dynamics or completely blocked. One of the principal advantages of the UTC structure is that a Doppler frequency derived from the INS is integrated with the tracking loops to improve the receiver tracking capability. The Doppler frequency shift is calculated and fed to the GPS tracking loops for elimination of the effect of stochastic errors caused by the Doppler frequency. In this paper, several nonlinear filtering approaches, including EKF, UKF, UPF and ‘FLAS assisted UPF’ (FUPF), are adopted for performance comparison for ultra-tight integration of GPS and INS. It is assumed that no outage occurs such that the inertial sensor errors can be properly corrected and accordingly the aiding information is working well. Two examples are provided for performance assessment for the various data fusion methods. The FUPF algorithm with Doppler velocity aiding demonstrates remarkable improvement, especially in the high dynamic environments, in navigation estimation accuracy with reduction of number of particles.

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

We previously mapped a psoriasis-susceptibility gene to a 3.8-Mb region of the 17q terminus in a five-generation Chinese family with autosomal-dominant psoriasis. To identify the mutations responsible for the psoriasis in this family, we sequenced 78 genes within the region and found four gene variants, p.Ala201Val in CD7 , c.-625A>C in zinc-finger protein 750 ( ZNF750 ), p.Asp189Asn in C17orf56 , and p.Ala568Thr in AATK cosegregated with the disease. The latter two variants were not studied further in the absence of disease segregation in other familial psoriasis and presence of variants in normal subjects. Functional analyses of CD7 did not support CD7 as a disease-causing gene. In contrast, the c.-625A>C mutation in ZNF750 resulted in a 42% reduction of the promoter activity, and the electrophoretic mobility shift assay showed binding of nuclear protein(s) to the mutant C allele. The c.-625A>C mutation was found in another sporadic psoriasis patient but was absent in 188 normal controls. Together, the mutation accounts for 1.7% (confidence interval: 0.2–5.84%) of psoriasis in the Chinese population. This report suggests that ZNF750 mutations could contribute to psoriasis susceptibility.

Total iodide organification defect (TIOD), where the iodide in the thyroid gland cannot be oxidized and/or bound to the protein, is caused by a defect in the thyroid peroxidase (TPO) gene. Single strand conformation polymorphism analysis was used to screen for mutations in the TPO gene from five unrelated TIOD patients in Taiwan, and five novel mutations were detected. Three of these were frameshift mutations: a single T insertion between nucleotide position 2268 and 2269 (c.2268-2269 insT) in exon 13 and two single C deletions at nucleotide positions 843 (c.843 delC) and 2413 (c.2413 delC) in exon 8 and 14 respectively. The other two were single nucleotide substitutions (c.G1477>A and c.G2386>T) located in exons 9 and 13 respectively. While the former would result in amino acid substitution (Gly493Ser) in the highly conserved region of the TPO polypeptide, the latter would result in either amino acid substitution (Asp796Tyr) or alternative splicing. Of those identified TPO mutations, c.2268-2269 insT was most prevalent and was detected as heterozygous in all but one TIOD patients. All five TIOD patients investigated in this study were compound heterozygous. The method presented in this study could be used for carrier assessment and mutation analysis of newly identified TIOD patients.

Background: Crouzon syndrome is an autosomal dominant disorder causing premature fusion of the cranial suture. Mutations have been reported in exon IIIa or IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Methods: In the present study, nine unrelated Crouzon syndrome patients were screened for mutations in the two exons of FGFR2 by polymerase chain reaction and direct sequencing. Results: Mutations were detected in 67% (6/9) of all cases. More than half the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel mutation, Tyr281Cys substitution, was discovered at exon IIIa. Conclusions: The mechanisms by which the same genotypes cause different phenotypes for each type of craniosynostosis syndrome in still uncertain. However, the molecular identification of the FGFR gene has made a great impact on the clinical classification of craniosynostosis syndromes; a new classification based on genotypes seems to be unavoidable.

Wilson disease (WND) is caused by a deficiency of the copper-transporting enzyme, P-type ATPase (ATP7B). Twelve different mutations have previously been identified in Taiwan Chinese with Wilson disease. We, herein, report another 4 missense mutations, 1 of which is novel. We did haplotype analysis of Taiwanese WND chromosomes, using three well characterized short tandem repeat markers (haplotype was assigned in the order of D13S314-D13S301-D13S316). Association correlation was found between the mutations and their respective haplotypes. Haplotype-deduced pedigree analysis was shown to be helpful in the mutation analysis of WND chromosomes and in the molecular assessment of both pre-symptomatic WND patients and carriers. Given the complexity and heterogeneity of the mutation spectrum of ATP7B, we suggest that haplotype analysis should be performed before full-scale mutation analysis.

Purpose To identify the genetic cause in five families with autosomal recessive retinitis pigmentosa, a genetic disorder involving retinal degeneration and visual loss with high genetic heterogeneity. Methods We performed whole-genome single nucleotide polymorphism genotyping on 35 members from the five families to map the region of homozygosity shared by all patients. Whole-genome sequencing was then conducted on one of the patients and a novel variant was identified in POMGNT1 from the homozygous region, which was confirmed by Sanger sequencing and sequenced in all family members. Mutant and wild-type POMGNT1 were expressed in heterologous cells to assess enzyme activity. Results A 1.8-Mb homozygous region was identified at 1p34-p33 shared by all 17 patients. Whole-genome sequencing revealed a novel missense mutation in POMGNT1 (c.359A>C, p.Leu120Arg) from this homozygous region, which was shown to co-segregate with disease phenotype. The mutant protein carrying this missense mutation showed an approximately 80% decrease in POMGNT1 enzyme activity compared with the wild type. Conclusions We identified a novel mutation in POMGNT1 that causes nonsyndromic autosomal recessive retinitis pigmentosa, adding to the genetic heterogeneity of this retinal disease. POMGNT1 encodes a glycosyltransferase in O-mannosyl glycosylation and was previously found to be responsible for a group of congenital muscular dystrophies called dystroglycanopathies. Our discovery suggests the involvement of O-mannosyl glycosylation in retinitis pigmentosa and presents an instance of POMGNT1 mutation that does not involve muscular dystrophy.

Background GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease caused by deficiency of acid beta-galactosidase (GLB1; EC3.2.1.23). Here, we identify three novel mutations in the GLB1 gene from two Han Chinese patients with GM1 that appear correlated with clinical phenotype. Methods One of the two Han Chinese patients with GM1 presented with the juvenile form, and the other with the infantile form with cardiac involvement. Sequencing of the entire GLB1 gene revealed three novel mutations (p.H102 D, p.G494V, c.495_497delTCT), which were absent in 94 normal controls. Transient expression of cDNA encoding these variants was performed in COS-1 cells to evaluate β-galactosidase activities. Results The first case (patient 1) with the juvenile form contained two missense mutations, p.H102 D and p.A301V. Patient 2 diagnosed with the infantile form of the disease with cardiac involvement was compound heterozygous for p.G494V and c.495_497delTCT mutations. All mutant beta-galactosidases exhibited significantly reduced activity (12%, 0%, 0%, and 0% for p.H102 D, p.A301V, p.G494V, and c.495_497delTCT), compared with the wild-type beta-galactosidase cDNA clone. The mutations identified in patient 2 with cardiomyopathy were localized in the GLB1 gene region common to both lysosomal beta-galactosidase and elastin binding protein (EBP), and caused a deletion in the elastin-binding domain of EBP. Conclusions All four mutations identified in Han Chinese patients induce significant suppression of β-galactosidase activity, correlating with severity of disease and presence of cardiomyopathy.

phi L7 is a lytic bacteriophage infecting Xanthomonas campestris pv. campestris, a Gram-negative bacterium producing xanthan gum and causing black rot in crucifers. A mutant resistant to phi L7 was isolated by Tn5 mutagenesis. Sequence analysis indicated that the gene responsible for the mutation is tonB encoding an inner membrane protein previously shown to be required for iron uptake and pathogenesis. This gene is clustered with three other genes, tonB-exbB-exbD1-exbD2. Results of insertional mutations, DNA and protein sequence analyses, phage sensitivity tests, transfection tests, complementation tests, and phage adsorption assays together with the cellular location of the proteins indicate that TonB, ExbB, and ExbD1 are essential for penetration of phage phi L7. The genome organization, structural features of the tonB-exb region, and transcriptional analyses including Northern hybridization, reporter assays, and primer extension together indicate that the four genes are organized into an operon.

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations., Author Summary Type 2 diabetes (T2D) is a complex disease that involves many genes and environmental factors. Genome-wide and candidate-gene association studies have thus far identified at least 19 regions containing genes that may confer a risk for T2D. However, most of these studies were conducted with patients of European descent. We studied Chinese patients with T2D and identified two genes, PTPRD and SRR, that were not previously known to be involved in diabetes and are involved in biological pathways different from those implicated in T2D by previous association reports. PTPRD is a protein tyrosine phosphatase and may affect insulin signaling on its target cells. SRR encodes a serine racemase that synthesizes D-serine from L-serine. Both D-serine (coagonist) and the neurotransmitter glutamate bind to NMDA receptors and trigger excitatory neurotransmission in the brain. Glutamate signaling also regulates insulin and glucagon secretion in pancreatic islets. Thus, SRR and D-serine, in addition to regulating insulin and glucagon secretion, may play a role in the etiology of T2D. Our study suggests that, in different patient populations, different genes may confer risks for diabetes. Our findings may lead to a better understanding of the molecular pathogenesis of T2D.

Type I oculocutaneous albinism (OCA1) is an autosomal recessive disorder, which is caused by the reduction or the absence of tyrosinase activity in melanocytes of the skin, hair and eyes. Although tyrosinase mutations of OCA1 have been extensively analyzed in most populations worldwide, there is no systemic study of OCA1 mutation in Chinese patients. By use of single strand conformation polymorphism and direct sequencing, we had detected 21 mutant alleles out of 24 OCA1 chromosomes screened (87.5%). Detected mutant alleles include one splicing site, three insertion/deletion and five missense mutations, of which the splicing site nucleotide alteration (IVS 1-3C>G) and two each of the insertion/deletion (232-233 ins GGG and 861-862 del TT) and missense mutations (Cys 289 Gly and Trp 400 Leu) are novel. The ins/del mutations accounts for about 37.5% in Chinese OCA1 alleles. The 232-233 ins GGG, one of the novel mutations, was found to be most frequent (25%) among the OCA1 alleles in Chinese. Through this study, we found that while some of the OCA mutant alleles were identified in other populations, ethnic difference still exists. Hum Mutat 14:542, 1999. © 1999 Wiley-Liss, Inc.